ovarian failure

Leukoencephalopathy with Vanishing White Matter

Clinical Characteristics
Ocular Features: 

Optic atrophy is a common feature and blindness is often the result.

Systemic Features: 

Onset of symptoms may occur at any time from 1.5 years of age to adulthood.  Early psychomotor development may be normal but developmental milestones such as walking and crawling are often delayed.  Patients with a later onset often have a milder course.  Progression is chronic but often episodic with exacerbations following infection and blunt head trauma. Mental stress, even of a relatively minor nature such as fright, may likewise cause a worsening of symptoms.  Such episodes can lead to loss of consciousness or even coma.  Cerebellar ataxia and spasticity are common.  Epilepsy may occur but is uncommon.  Motor function is more severely impaired compared with mental deterioration.  The MRI reveals a diffuse leukoencephalopathy as well as focal and cystic degeneration of white matter which may be present before the onset of symptoms.  Cerebellar atrophy primarily involving the vermis is common.  Behavioral problems, psychiatric symptoms, and even signs of dementia have been reported.  The vast majority of patients have cognitive disabilities and many become severely handicapped and immobile.  Early onset disease in children often leads to death within a few years whereas adults with later onset may live for many years.       

Females with leukoencephalopathy who live to puberty may experience ovarian failure, a condition sometimes called ovarioleukodystrophy.

Genetics

This is an autosomal recessive disorder secondary to homozygous mutations in one of a group of five genes (EIF2B) located on chromosomes 1,2,3,12, and 14 encoding subunits of translation initiation factor 2B.    

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no effective treatment for the neurologic disease.  Ocular treatment for cataracts has not been reported.

References
Article Title: 

Galactokinase Deficiency

Clinical Characteristics
Ocular Features: 

This is a considerably more rare disorder of galactose metabolism compared with classic galactosemia (230400).  Both disorders cause cataracts in the neonatal period but the early systemic effects of galactokinase deficiency are less severe.  In the latter disorder, cataracts usually develop later, often during the first decade of life and less commonly during the neonatal period that is characteristic of classic galactosemia.  Galactitol  accumulation causing osmotic changes in the lens accounts for the cataracts and may also be responsible for the development of pseudotumor cerebri found infrequently.  Good dietary control may prevent the formation and progression of cataracts and it has been reported that they may regress as well but only prior to the rupture of cell membranes.

Systemic Features: 

Late complications include abnormalities in mental and/or motor development, dyspraxia, and hypogonadotropic hypogonadism which occur in spite of severe reduction in galactose intake.  Ovarian failure is common.

Genetics

This is an autosomal recessive disorder caused by mutations in the GALK1 gene (17q24) encoding galactokinase.  It is extremely rare but should be considered in any patient with cataracts found within the first two decades of life.  Deficient activity of the galactokinase enzyme can be demonstrated in erythrocytes.

For other disorders of galactose metabolism, see galactosemia (230400) and galactose epimerase deficiency (230350).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Early dietary restriction of non-galactose polycarbohydrates and deficient in lactose may prevent the formation of cataracts or sometimes result in regression.

References
Article Title: 

Galactosemia

Clinical Characteristics
Ocular Features: 

Neonatal cataracts are found among at least 30% of infants with this disorder.  However, early (before 17 days of age) dietary restrictions can prevent their formation or even lead to regression.  They result from the osmotic imbalance caused by the presence of accumulated galactitol.  Neonates may suffer vitreous hemorrhages from the coagulopathy but this is rare.

Systemic Features: 

In spite of early and adequate treatment, however, many adults have residual problems.  Cataracts have been found in 21%, decreased bone density in 24%, tremor in 46%, ataxia in 15%, and dysarthria in 24%.  Few patients of either sex have children and all females have premature ovarian insufficiency.  Depression and anxiety are present in 39-67%.  It has been estimated that there is a twofold increase in the odds of depression with each 10 year increment of age.

Genetics

This is an autosomal recessive disorder resulting from mutations in the GALT gene (9p13) encoding galactose-1-phosphate uridylyltransferase.

For other disorders of galactose metabolism see galactose epimerase deficiency (230350) and galactokinase deficiency (230200).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Treatment with a lactose- and galactose-free diet within the first 3-17 days can prevent the formation of cataracts.  Few need surgical removal.  Liver function improves and a reduction in icterus can be seen.  It can also prevent fatal E. coli sepsis.  However, long term effects have been disappointing as many patients still develop mental and motor dysfunction as well as speech difficulties (dyspraxia).  The long term outcome seems to depend upon the level of GALT enzyme activity which varies considerably.

Special education and speech therapy may be beneficial.  Depression in older patients should be offered where indicated.

References
Article Title: 

The adult galactosemic phenotype

Waisbren SE, Potter NL, Gordon CM, Green RC, Greenstein P, Gubbels CS, Rubio-Gozalbo E, Schomer D, Welt C, Anastasoaie V, D'Anna K, Gentile J, Guo CY, Hecht L, Jackson R, Jansma BM, Li Y, Lip V, Miller DT, Murray M, Power L, Quinn N, Rohr F, Shen Y, Skinder-Meredith A, Timmers I, Tunick R, Wessel A, Wu BL, Levy H, Elsas L, Berry GT. The adult galactosemic phenotype. J Inherit Metab Dis. 2011 Jul 21. [Epub ahead of print]

PubMed ID: 
21779791

BPES Syndrome

Clinical Characteristics
Ocular Features: 

This is primarily a dysplasia of the eyelids and adnexae.  The acronym is derived from the longer title sometimes used: blepharophimosis, ptosis, and epicanthus inversus syndrome.  The palpebral fissures are small and the curve of the epicanthal fold is mediolateral, but below the medial canthus.  The nasal bridge is flat or at least low, and the lids are ptotic.  Telecanthus may be present as well.  Refractive errors, strabismus, nystagmus, and amblyopia are often associated.  Entropion with trichiasis may require surgical attention.  Mutations in the FOX family of genes are associated with a wide variety of ocular anomalies including microcornea, trabecular dysgenesis, optic nerve hypoplasias and colobomas that are sporadically present in BPES syndrome.

Alacrima is a feature in many cases, caused by hypoplasia or aplasia of the major lacrimal gland.

Systemic Features: 

This condition is sometimes associated with ovarian failure although breast development is often normal.  The resultant infertility is an example of a sex-limited autosomal trait.  The syndrome can result from cytogenetic aberrations as well but individuals with these usually have other malformations such as contractures, mental defects, microcephaly, growth retardation, etc.

Some authors have considered individuals with the typical features of BPES who also have genitourinary malformations and cognitive deficits as examples of BPES plus syndrome.  A recent report, for example, describes two sibs, a male and a female, with some features of this syndrome plus posteriorly rotated ears, hypertelorism, telecanthus, micrognathia and severe psychomotor retardation.  The responsible mutation was not identified and its relationship to BPES remains unknown.  Another individual with typical ocular and systemic features of BPES in addition to cryptorchidism, developmental delay, and syndactyly, was found to have a mutation in the gene KAT6B in the absence of mutations in FOXL2. 

The phenotypic spectrum of this condition is extensive and it is likely that multiple mutations are collectively responsible for the clinical heterogeneity.

Genetics

This is an autosomal dominant condition with sex-limited characteristics in females (infertility, small uterus, atrophic ovaries).  The karyotype in females is normal.  It is one of the rare conditions with an apparent maternal age effect, at least in sporadic cases which are not uncommon. 

Mutations in the FOXL2 gene at 3q23 seem to be responsible for at least some familial cases. It codes for a gene active in the mesenchyme of the eyelids and in the ovarian follicle, at least in mice.  About 12% of patients do not have a FOXL2 mutation though. Numerous mutations have been found, some of which cause premature ovarian failure (sometimes labeled BPES type I) while others cause only lid maldevelopment (BPES type II).

A mutation in KAT6B (10q22.2) has been found in a single individual with features typical of BPES in whom no FOXL2 mutations were present.  It has been suggested that BPES patients without mutations in FOXL2 should be sequenced for mutations in KAT6B. 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Lid surgery might be helpful in some patients with severe ptosis and/or trichiasis.

References
Article Title: 
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